Stabilized Atypical Antipsychotic Formulation

ABSTRACT

A pharmaceutical composition that contains an atypical antipsychotic drug and succinic acid, fumaric acid or a mixture of succinic acid and fumaric acid.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/083,270 filed on Jul. 24, 2008.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stabilized pharmaceutical compositioncomprising an atypical antipsychotic drug and at least one organic acidselected from the group consisting of succinic acid, fumaric acid, ormixtures thereof. In particular, the present invention relates to apharmaceutical composition that contains a diazepine, an oxazepine or athiazepine atypical antipsychotic drug and at least one organic acidselected from the group consisting of succinic acid, fumaric acid ormixtures thereof. The composition should exhibit a pH of less than 5,preferably less than 4 when the composition is placed in sufficientwater to create a 1% weight by volume solution or suspension atapproximately 25° C.

BACKGROUND OF THE INVENTION

Atypical antipsychotic drugs are a class of drugs used to treatpsychiatric conditions such as schizophrenia, acute mania and bipolardisorders. Some of the early or typical antipsychotic drugs exhibited anumber of undesirable side effects such as acute dyskinesias, acutedystonias, motor restlessness, pseudo-Parkinsonism andtardivedyskinesias. These adverse side effects have been referred to asextrapyramidal symptoms.

In an effort to overcome these extrapyramidal symptoms, a group ofcompounds were developed that are commonly referred to as atypicalantipsychotic drugs. These atypical antipsychotic drugs are generallyheterocyclic compounds that affect the serotonin and dopamine receptors.Examples of some atypical antipsychotic drugs include clozapine,olanzapine, risperidone, quetiapine, ziprasidone, paliperidone,aripiprazole, asenapine, iloperidone, sertindole, zotepine, amisulpridebifeprunox, melperone and pharmaceutically acceptable salts thereof.

Pharmaceutical dosage forms containing atypical antipsychotic drugs havebeen described in the literature. For example, the 61^(st) edition ofthe Physicians' Desk Reference, ® 2007 (“PDR”), describes commerciallyavailable RISPERDAL® products which are oral solutions, tablets, orallydisintegrating tablets and microsphere-containing injections thatcontain risperidone (see PDR at pages 1676-1688); ABILIFY® productswhich are oral solutions, tablets and orally disintegrating tablets thatcontain aripiprazole (see PDR at pages 2450-2455) and GEODON® capsulesand injections. Some of these formulations employ organic acids such ascitric, tartaric and benzoic acids.

U.S. Pat. No. 5,563,134 discloses clozapine dosage forms that contain anacid scavenger such as ascorbic acid. The ascorbic acid is reported toreduce the occurrences of granulocytopenia or agranulocytosis that isknown to occur with the administration of clozapine. U.S. Pat. No.6,251,895 discloses olanzapine dosage forms that contain benzoic acid.Olanzapine is also commercially available under the tradename ZYPREXA®in an intramuscular formulation that employs tartaric acid.

U.S. Pat. No. 5,948,437 discloses a number of quetiapine dosage formsand indicates organic acids or alkali metals salts of the organic acidsmay be used as pH modifiers in the dosage forms. Although a number oforganic acids are disclosed in this patent, it is reported that thealkali metal salts such as sodium citrate are preferred.

Although many pharmaceutical dosage forms containing atypicalantipsychotic drugs have been described in the art, it is an object ofthe present invention to provide a pharmaceutical composition comprisingan atypical antipsychotic drug and an organic acid selected from thegroup consisting of succinic acid, fumaric acid or mixtures thereof. Itis believed that the use of these non-metal, dual carboxyl group organicacids improve the stability of the atypical antipsychotic drug.

It is another object of the present invention to provide apharmaceutical dosage form comprising an atypical antipsychotic drug andan organic acid selected from the group consisting of succinic acid,fumaric acid or mixtures thereof that can be administered orally.

It is yet another object of the present invention to provide acontrolled release pharmaceutical dosage form comprising an atypicalantipsychotic drug and an organic acid selected from the groupconsisting of succinic acid, fumaric acid or mixtures thereof.

It is still a further object of the present invention to provide acontrolled release pharmaceutical dosage form comprising an atypicalantipsychotic drug and an organic acid selected from the groupconsisting of succinic acid, fumaric acid or mixtures thereof that isfree of any swelling or hydrogel polymeric materials.

These and other objects of the present invention will become apparentfrom a review of the appended specification.

SUMMARY OF THE INVENTION

The present invention accomplishes the above objects and others byproviding a novel pharmaceutical composition comprising an atypicalantipsychotic drug and an organic acid selected from the groupconsisting of succinic acid, fumaric acid or mixtures thereof. Thecomposition should exhibit a pH of less than 5, preferably less than 4,when a 1% weight by volume aqueous solution or suspension is prepared at25° C.

In one embodiment of the present invention, the succinic acid, fumaricacid or mixture thereof should comprise at least about 5 weight percentof the composition, preferably at least about 10 weight percent of thecomposition and most preferably at least about 20 weight percent of thecomposition.

The composition may be an intermediate composition or a finalformulation or dosage form. The composition should also comprise atleast one additional pharmaceutical excipient.

One embodiment of the present invention is a solid composition.

In an alternate embodiment of the present invention, the composition isa controlled release formulation that comprises an atypicalantipsychotic drug, an organic acid selected from the group consistingof succinic acid, fumaric acid or mixtures thereof and a ratecontrolling excipient. The rate controlling excipient can be a filmforming polymer that forms a coating or barrier around the formulationor a matrix forming material. A further embodiment of the controlledrelease formulation comprises an atypical antipsychotic drug, an organicacid selected from the group consisting of succinic acid, fumaric acidor mixtures thereof and a hydrophobic matrix material, i.e., anon-swelling and/or non-gelling matrix material.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention concerns a stable pharmaceutical compositioncomprising an atypical antipsychotic drug and an organic acid selectedfrom the group consisting of succinic acid, fumaric acid or mixturesthereof. Examples of atypical antipsychotic drugs that may be used inthe present invention include clozapine, olanzapine, risperidone,quetiapine, ziprasidone, paliperidone, aripiprazole, asenapine,iloperidone, sertindole, zotepine, amisulpride bifeprunox, melperone andpharmaceutically acceptable salts, isomers and metabolites of theaforementioned drugs. A more complete list of atypical antipsychoticdrugs can be found in Remington: The Science and Practice of Pharmacy,20^(th) edition and in the United States Pharmacopeia 29, both of whichare incorporated herein by reference.

A preferred group of the atypical antipsychotic drugs useful in thepresent invention include the diazepines, oxazepines and thiazepines andpharmaceutically acceptable salts thereof. The more preferred group ofatypical antipsychotic drugs useful in the present invention areolanzapine and quetiapine as described in U.S. Pat. Nos. 5,229,382;5,627,178; 6,251,895 and 4,879,288, which are incorporated herein byreference. The most preferred atypical antipsychotic drugs arepharmaceutically acceptable salts of quetiapine such as the fumarate andhydrochloride salts.

The amount of antipsychotic drug employed in the dosage forms preparedin accordance with the present invention can range from 0.25 mg to 500mg. The amount in the final dosage forms will vary depending upon theatypical antipsychotic drug selected and the dosage form containing thedrug. It is within the ordinary skill in the art to determine theappropriate amount of atypical antipsychotic drug based upon thereported therapeutic amounts for the known antypical antipsychoticdrugs.

The present invention will also comprise an organic acid selected fromthe group consisting of succinic acid, fumaric acid and mixturesthereof. Succinic acid is also known as amber acid, ethylenesuccinicacid, and 1,4-butanedioic acid. Succinic acid can be prepared byhydrogenation of maleic or fumaric acid or by aqueous alkali or acidhydrolysis of succinonitrile. It is reported in the Merck Index that 1gram of succinic acid can dissolve in 13 ml of cold water and 1 ml ofboiling water. The United States Food and Drug Administration (FDA) hasidentified succinic acid as a GRAS compound (generally recognized assafe) when used as a food additive in small amounts. For example, 21C.F.R. §184.1091 identifies succinic acid as a flavor enhancer and a pHcontrol agent.

Fumaric acid is also known as (E)-butenedioic acid,trans-1,2-ethylenedicarboxylic acid, 2-butenedioic acid, allomaleicacid, boletic acid, lichenic acid and trans-butenedioic acid. The MerckIndex indicates that 0.63 grams of fumaric acid are soluble in 100 gramsof water at 25° C. Fumaric acid has been used as a flavor enhancingagent and a pH modifying agent.

Compositions in accordance with the present invention should exhibit apH of less than 5, preferably less than 4 when a 1% weight by volumeaqueous solution or suspension is prepared and measured at 25° C. In oneembodiment of the present invention, the composition should exhibit a pHbetween 2 and 5, preferably between 2.5 and 4.5 and most preferablybetween 3 and 4 when a 1% weight by volume aqueous solution orsuspension of the composition is prepared and measured at 25° C.

Embodiments of the present invention may comprise about 5 to about 95weight percent, preferably about 10 to about 90 weight percent of thecomposition and most preferably about 15 to about 85 weight percent ofthe composition of the succinic acid, fumaric acid or mixture ofsuccinic and fumaric acid.

In certain embodiments of the present invention, such as solid oraldosage forms, the solid oral dosage form should exhibit a pH between 2and 5, preferably between 2.5 and 4.5 and most preferably between 3 and4 when a 1% weight by volume aqueous solution or suspension of thedosage form ingredients is prepared and measured at 25° C. comprises.These solid oral dosage forms typical comprise at least about 5 weightpercent of the organic acid selected from succinic acid, fumaric acid ormixtures thereof, preferably at least about 10 weight percent and mostpreferably at least about 15 weight percent. In certain controlledrelease dosage forms prepared in accordance with the present invention,it has been discovered that the succinic acid, fumaric acid or mixtureof succinic acid and fumaric acid should comprise at least 20 weightpercent of the total weight of the controlled release dosage form,preferably at least 25 weight percent and most preferably at least 27.5weight percent.

The ratio of atypical antipsychotic drug to organic acid in thepharmaceutical composition prepared in accordance with the presentinvention should be about 5:1 to 1:5 and preferably about 3:1 to 1:3depending upon the atypical antipsychotic drug selected.

The present invention should also include at least one additionalpharmaceutically acceptable excipient. The pharmaceutically acceptableexcipients useful in the present invention can be selected from thegroup consisting of fillers, binders, lubricants, glidants,antiadherents, flavoring agents, coloring agents, disintegrants andmixtures of thereof. A more detailed description of the acceptablepharmaceutical excipients that may be employed in the present inventioncan be found in Rowe et al., Handbook of Pharmaceutically AcceptableExcipients (4^(th) ed. 2003) or the United States Pharmacopeia 29, bothof which are incorporated herein by reference.

Examples of acceptable fillers, sometimes referred to as diluents,include water; sugars such as lactose, dextrose, sucrose, maltose, ormicrocrystalline cellulose; clays and mixtures thereof.

Binders that are useful in the present invention includepharmaceutically acceptable substances with cohesive properties. Someexamples include celluloses such as hydroxypropyl methycellulose,hydroxypropyl cellulose and carboxymethycellulose sodium;polyvinylpyrrolidone; sugars; starches and mixtures thereof.

Examples of lubricants, glidants and/or antiadherents that may be usedin the present invention include talc, magnesium stearate, calciumstearate, stearic acid, hydrogenated vegetable oils, polyethyleneglycols, silicon dioxide and mixtures thereof.

Flavoring agents that can be used in the present invention includepeppermint, spearmint, wintergreen, cinnamon, coconut, coffee,chocolate, vanilla, menthol, liquirice, anise, apricot, caramel,pineapple, strawberry, raspberry, grape, cherry, mixed berry, tropicalfruits, mint and mixtures thereof.

Coloring agents that may be employed in the present invention includeFD&C-type dyes and lakes, fruit and vegetable extracts, titantiumdioxide and mixtures thereof.

Examples of disintegrating agents that can be used in the presentinvention include corn starch, croscarmelose sodium, crospovidone(polyplasdone XL-10), sodium starch glycolate (EXPLOTAB or PRIMOJEL) orany combination of the foregoing.

The pharmaceutical composition of the present invention can be any typeof composition known in the pharmaceutical arts such as a solution,suspension, emulsion or solid. The composition can be an intermediateused in the manufacture of a dosage form or may be a dosage formdesigned for parental, intravenous, ophthalmic, oral, buccal, rectal orvaginal delivery. The preferred embodiment of the present invention is asolid oral dosage form such as an orally disintegrating tablet, animmediate release dosage form, a delayed or enteric coated dosage form,a controlled release dosage form or a combination of the forgoing.

An immediate release dosage form in accordance with the presentinvention may be prepared using techniques commonly known in the art andcan be in the form of a tablet or capsule.

In forming an immediate release tablet in accordance with the presentinvention, an atypical antipsychotic drug, an organic acid selected fromthe group consisting of succinic acid, fumaric acid or mixtures thereofand at least one additional excipient such as a binder, filler andlubricant are mixed together using standard techniques known in the artsuch as blending, slugging and/or granulation. The mixture can becompressed into tablets using techniques commonly used in the art. Oncethe mixture has been compressed and formed into a tablet core, it mayoptionally be coated with a seal coating or an aesthetic coating. Theseal coating or aesthetic coating typically is a coating or layer thatis soluble or rapidly disintegrating in water and does not materiallyaffect the release of the active ingredients from the tablet core. Themost common seal coatings comprise low molecular weight hydroxypropylmethylcellulose or polyvinyl alcohol. Some typical seal coats aredescribed in U.S. Pat. Nos. 4,786,505; 6,099,859 and 5,314,697, whichare incorporated herein by reference.

An immediate release composition in accordance with the presentinvention may also be prepared by blending an atypical antipsychoticdrug, organic acid selected from the group consisting of succinic acid,fumaric acid or mixtures thereof and at least one additional excipientsuch as a filler and loading the blended mixture into a gelatin capsule.

The following table provides a representative composition that can beprepared in accordance with the present invention:

TABLE 1 Materials Preferred Most Preferred Atypical Antipsychotic0.5-75%   1-50% Drug Organic Acid(s)  5-75% 20-60% Filler  5-70% 10-65%Glidant 0-5% 0.1-3%   Lubricant 0-5% 0.1-3%  

The above percentages are based upon the total weight of thecomposition. The above composition can be further processed into adosage form such as a tablet or capsule.

A controlled release dosage form in accordance with the presentinvention may also be prepared using techniques commonly known in theart. Some of the controlled release dosage forms that are useful in thepresent invention include, but are not limited, to matrix tablets,osmotic tablets, pellet filled capsules or combinations of theforegoing. Release controlling excipients such as hydrophilic andhydrophobic matrix polymers and polymeric coatings are known in the artand described in Rowe et al., Handbook of Pharmaceutically AcceptableExcipients (4^(th) ed. 2003), which is incorporated herein by reference.The controlled release dosage form in accordance with the presentinvention should release therapeutically effective amounts of theatypical antipsychotic drug over a period of 4-24 hours, preferably 8-24hours, so the dosage form can be administered once or twice daily.

One embodiment of a controlled release dosage form in accordance withthe present invention is a matrix tablet. The matrix tablet shouldcomprise therapeutically effective amount of the atypical antipsychoticagent, a stabilizing amount of an organic acid selected from the groupconsisting of succinic acid, fumaric acid or mixtures thereof and amatrix forming agent. The matrix forming agent can be a hydrophobicmaterial such as a wax, a hydrophilic material such as a hydrogelpolymer or a combination of the two. As used herein, a hydrogel polymeris a polymeric material that gels or swells when placed in an aqueousenvironment. The matrix forming agent will control the release of theatypical antipsychotic drug by diffusion of the drug from the matrix,erosion of the matrix or a combination of diffusion and erosion. Theamount of diffusion and erosion will depend upon the materials selectedfor the formation of the matrix.

Examples of hydrogel forming polymers include hydroxypropylmethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulosesodium, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,methyl cellulose, acrylic polymers and copolymers, sodium alginate,polyethylene oxides and mixtures thereof.

Examples of hydrophobic materials that can be used to form a non-gellingor non-swelling controlled release matrix for the atypical antipsychoticdrug include beeswax, white wax, emulsifying wax, hydrogenated vegetableoil, hydrogenated castor oil, microcrystalline wax, cetyl alcohol,stearyl alcohol, free wax acids such as stearic acid, esters of waxacids, propylene glycol monostearate, glycerol monostearate, carnaubawax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax,lardaceine, China wax and mixtures thereof. Other possible ratecontrolling excipients useful in the present invention include saturatedhydrocarbons having from 25 to 31 carbon atoms, saturated alcoholshaving from 25 to 31 carbon atoms, saturated monocarboxylic acids havingfrom 25 to 31 carbon atoms, esters obtained from said alcohols andmonocarboxylic acids which are described in U.S. Pat. No. 6,923,984,incorporated herein by reference.

A combination of hydrophobic and hydrophilic materials may also be usedin preparing a controlled release matrix of the present invention.

The controlled release matrix in accordance with the present inventionmay further comprise conventional excipients that improve the processingor modify the release characteristics. Examples of these conventionalexcipients include fillers, glidants and lubricants describedpreviously.

One embodiment of the controlled release matrix dosage form inaccordance with the present invention and without a gelling or swellingpolymer should comprise the following composition:

Preferred Most Preferred Ingredient % w/w % w/w Atypical Antipsychotic25-75 35-65 Organic Acid(s) 15-60 20-50 Hydrophobic Rate ControllingExcipient  1-25  3-15 Filler 0.5-25   1-15 Lubricant/Glidant  0-150.1-10 

The above-described hydrophobic matrix tablet may also comprise aplacebo layer or layers applied to one or more surfaces of thehydrophobic matrix tablet. The placebo layer is designed to reduce thesurface area of the hydrophobic matrix tablet when the tablet is exposedto the environment of use. The reduction in surface area contributes tocontrolling the release of the atypical antipsychotic drug from thehydrophobic matrix. The placebo layer may comprise any of theaforementioned hydrophobic or hydrophilic matrix materials, although thehydrophobic materials are preferred. The placebo layer should coverabout 5% to about 75%, preferably about 10% to about 65% and mostpreferably about 15% to about 50% of the surface area of the hydrophobicmatrix tablet.

Once the matrix tablet has been formed, it may optionally be seal coatedor coated with an aesthetic coating as described above with respect tothe immediate release composition.

An immediate release coating comprising the atypical antipsychotic drugcan be coated directly onto the controlled release matrix core orapplied over the sealed coated controlled release matrix core. Theimmediate release coating comprises the atypical antipsychotic drug anda film forming material or binder and, optionally, other conventionaladditives such as lubricants, fillers and antiadherents.

The immediate release coating may be applied by any conventionaltechnique such as pan coating or spray coating. In the preferredembodiment, the immediate release coating is applied by spraying anaqueous solution or suspension over a pan containing the matrix cores.The film forming material or binder employed in the immediate releasecoating is preferably a water soluble or rapidly dispersing materialsuch as a low molecular weight hydroxypropyl methylcellulose orpovidone.

Another embodiment of the controlled release dosage form in accordancewith the present invention is an osmotic tablet. The osmotic tablet maycomprise: a core containing a therapeutic amount of the atypicalantipsychotic drug and organic acid selected from the group consistingof succinic acid, fumaric acid or mixtures thereof; a semi permeablemembrane surrounding the core; and a passageway in the semi permeablemembrane for release of the drug.

The core of the osmotic tablet can be prepared with or without a gellingor swelling polymer. The core of the osmotic tablet can be a homogenousblend of atypical antipsychotic drug, organic acid selected fromsuccinic acid, fumaric acid or mixtures thereof and pharmaceuticalexcipients as described in U.S. Pat. No. 5,654,005 or a multilayeredstructure comprising a drug composition and a push composition asdescribed in U.S. Pat. Nos. 4,612,008 or 4,873,337. The aforementionedpatents are incorporated herein by reference.

The osmotic core can optionally be seal coated prior to the applicationof the semipermeable membrane. The semi permeable membrane should bepermeable to the passage of an external fluid such as water or aqueousbiological fluids and should be impermeable to the passage of the activeingredients in the osmotic core. Materials that are useful in formingthe semi permeable membranes are ethylcellulose, cellulose esters,cellulose diesters, cellulose triesters, cellulose ethers, celluloseester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate and cellulose acetate butyrate.Other suitable polymers are described in U.S. Pat. Nos. 3,845,770;3,916,899; 4,008,719; 4,036,228 and 4,612,008, which are incorporatedherein by reference. The most preferred semi permeable membrane materialis cellulose acetate comprising an acetyl content of 39.3% to 40.3%, andis commercially available from Eastman Fine Chemicals.

In an alternative embodiment, the semipermeable membrane can include oneof the above-described polymers and a flux-enhancing agent. Theflux-enhancing agent can increase the volume of fluid imbibed into thecore to enable the composition to dispense substantially all of theactive ingredients through the passageway and/or the pores created inthe membrane by the dissolution of the flux-enhancing agent. Theflux-enhancing agent can be a water-soluble material or an entericmaterial. Examples of the preferred materials that are useful as fluxenhancers are sodium chloride, potassium chloride, sucrose, sorbitol,mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropylcellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulosephthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylicacid copolymers, poloxamers (such as LUTROL F68, LUTROL F127, LUTROLF108, which are commercially available from BASF) and mixtures thereof.A preferred flux enhancer is PEG 400.

The flux-enhancing agent comprises approximately 0% to about 40% of thetotal weight of the membrane coating, most preferably about 2% to about20% of the total weight of the membrane coating. The flux-enhancingagent dissolves or leaches from the semipermeable membrane to form pathsin the semipermeable membrane which enables fluid to enter the osmoticcore and dissolve the atypical antipsychotic drug.

The semipermeable membrane may also be formed using a commonly knownexcipient such as a plasticizer. Some commonly known plasticizersinclude adipate, azelate, enzoate, citrate, stearate, isoebucate,sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butylcitrate, citric acid esters, and those described in the Encyclopedia ofPolymer Science and Technology, Vol. 10 (1969), published by John Wiley& Sons. The preferred plasticizers are triacetin, acetylatedmonoglyceride, grape seed oil, olive oil, sesame oil,acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate and combinations thereof. Dependingon the particular plasticizer, amounts from about 0% to about 25%, andpreferably about 2% to about 15%, of the plasticizer can be used basedupon the total weight of the membrane coating.

Generally, the membrane coating around the core will comprise from about1% to about 5%, and preferably about 2% to about 3%, based upon thetotal weight of the core and coating.

In a preferred embodiment, the membrane coating surrounding the corefurther comprises a passageway that will allow for controlled release ofthe drug from the core. As used herein, the term “passageway” includesan aperture, orifice, bore, hole, weakened area or an erodible elementsuch as a gelatin plug that erodes to form an osmotic passageway for therelease of the active ingredients from the dosage form. Passageways usedin accordance with the subject invention are well known and aredescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407;4,783,337 and 5,071,607, which are incorporated herein by reference.

An immediate release coating(s) may be applied to the semipermeablemembrane. The immediate release coatings are described above and may beapplied by, but would not be limited to, the processes selected from thegroup consisting of drug layering, lamination or dry compression. In apreferred embodiment, a seal coat is applied to the semi-permeablemembrane before the immediate release layer is applied.

Another embodiment of the controlled release dosage form in accordancewith the present invention comprises beads, pellets or mini-tabletscomprising the active ingredients. The beads, pellets or mini-tabletsmay be filled into hard or soft gelatin capsules or compressed into atablet.

The bead, pellets or mini-tablets are prepared by methods commonly knownin the art and typically range in size from about 0.1 mm to about 3 mmin diameter. Ideally, the beads or pellets are about 0.2 to about 1 mmin diameter and the mini-tablets are about 0.5 to about 2.5 mm indiameter.

Active or immediate release beads or pellets are prepared by layering acomposition in accordance with the present invention onto an inertsubstrate such as a non-pariel seed or a microcrystalline cellulose seedcommercially available under the tradename CELPHERE®. Active beads orpellets can also be prepared by preparing a composition in accordancewith the present invention and subjecting the composition to extrusionspheronization techniques. The composition should comprise a mixture ofan atypical antipsychotic drug, organic acid selected from the groupconsisting of succinic acid, fumaric acid or mixtures thereof and atleast one additional conventional pharmaceutical excipient such as abinder and/or filler. The mixture of active ingredients and conventionalpharmaceutical excipients can also be compressed in mini-tablets. Theactive or immediate release beads or pellets can be also prepared by themethods described in U.S. Pat. No. 5,529,791 and 4,984,240, which areincorporated herein by reference.

Once the active or immediate release beads, pellets or mini-tablets areprepared, they may be coated with a release controlling polymer coating.The controlled release coating should comprise a water insoluble, waterpermeable polymer and, optionally, a water or acid soluble channelingagent. The controlled release coating may also comprise a lubricating ordusting agent and, optionally, a surfactant.

Suitable water insoluble, water permeable polymers are ethylcellulose,cellulose acetate and polyacrylates or mixtures thereof. Additionalwater insoluble polymers are described in U.S. Pat. No. 5,002,776 whichis incorporated herein by reference.

One embodiment of the controlled release bead, pellet or mini-tabletdosage form of the present invention employs a water insoluble, waterpermeable polymer coating such as a polymethacrylate ester copolymer,preferably a poly(ethylacrylate methylmethacrylate) copolymer which iscommercially available from Rohm Pharma under the tradename EUDRAGIT NE30D.

The channeling agent employed in the bead, pellet or mini-tablet coatingcan be any type of water or acid soluble pharmaceutically acceptablesubstance commonly known in the art such as polyvinyl pyrrolidone,hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sucrose or any combination of the foregoing. Thepreferred channeling agent is a water or acid soluble polymer such as alow viscosity hydroxypropyl methylcellulose.

Suitable surfactants that may optionally be used in the controlledrelease coating for the beads, pellets or mini-tablets are sodium laurylsulfate, sodium taurocholate or a polysorbate.

The controlled release coating can be applied to the active beads,pellets or mini-tablets by any means commonly known in the industry suchas a rotary granulator, pan coater or a fluidized bed coater.

Once the bead, pellets or mini-tablets are coated they may be dustedwith a suitable lubricant such as talc, magnesium stearate, silicondioxide, kaolin or a mixture of the foregoing. The lubricant willprevent the beads, pellets or mini-tablets from sticking to one anotherduring processing.

In one embodiment of the present invention, the active or immediaterelease beads, pellets or mini-tablets comprising the atypicalantipsychotic drug and organic acid selected from the group consistingof succinic acid, fumaric acid or mixtures thereof are prepared. Aportion of the active or immediate release beads, pellets ormini-tablets are then subsequently coated with a controlled releasecoating. Various blends of the active and controlled release coatedbeads, pellets or mini-tablets are blended and filled into hard gelatincapsules. For example, a blend of 20% active beads and 80% controlledrelease beads are filled into a hard gelatin capsule to prepare aonce-a-day capsule dosage form in accordance with the present invention.

A delayed release dosage form in accordance with the present inventionmay also be prepared by first preparing an immediate release tabletcore, a controlled release matrix core or active bead, pellet ormini-tablet core as described above. The cores are then coated with anenteric or pH sensitive coating using techniques commonly known in theart.

The enteric or pH dependent coating material useful in preparing adelayed release coating include zein, shellac, methacrylic acidcopolymers, cellulose acetate phthalate, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, celluloseacetate trimellitate, polyvinyl acetate phthalate or mixtures thereof.

The delayed release coating should be applied so that the atypicalantipsychotic drug present in the core is released only after thecomposition has passed through the stomach. To insure that the atypicalantipsychotic drug present in the core is not released until thecomposition has left the stomach, the delayed release coating should bedesigned to dissolve at a pH greater than 4.5, preferably greater than5.5 and most preferably greater than a pH of 6.

The delayed release coating may also comprise plasticizers and otherconventional processing aids as described above.

The delayed release dosage form in accordance with the present inventionmay also comprise an immediate release component. For example, in thecase of a delayed release tablet, the enteric or pH dependent coatedtablet may be coated with an immediate release layer as describedpreviously. In the case of enteric coated pellets, a blend of entericcoated pellets and immediate release pellets can be blended together andfilled into a hard gelatin capsule or compressed into a tablet. Thecombination of enteric or pH coated compositions and immediate releasecomponent will allow the pulsatile delivery of the atypicalantipsychotic drug from a single dosage form.

The pharmaceutical compositions and dosage forms prepared in accordancewith the present invention should contain less than 0.5 weight percentof total active ingredient impurities based upon the total weight of thecomposition or dosage form, preferably less than 0.3 weight percent andmost preferably less than 0.25 weight percent of total active impuritieswhen the composition or dosage form is placed in an open container andexposed to 60% relative humidity and 60° C. for two weeks.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following are provided by way of example only and are by no meansintended to be limiting.

EXAMPLE 1

A composition in accordance with the present invention was prepared bymixing equal amounts of quetiapine fumarate and succinic acid, i.e., 1:1ratio. The composition was placed in an open container and subjected toaccelerated stability conditions of 60° C. and 60% humidity for twoweeks. The impurity profile of the composition was determined by HPLC asfollows:

% Unknown Impurity with RRT* 0.47 Time point Sample 1 Sample 2 Averageinitial 0.0332 0.0336 0.0334 1 week 0.0301 0.0312 0.0307 2 weeks 0.03500.0382 0.0366 *RRT = relative retention time

% Unknown Impurity with RRT* 0.59 Time point Sample 1 Sample 2 Averageinitial Below Detectable Below Detectable Below Detectable limits limitslimits 1 week 0.0183 0.0179 0.0181 2 weeks 0.0300 0.0312 0.0306 *RRT =relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0682 0.0695 0.0689 1 week 0.0721 0.0716 0.0719 2 weeks 0.08070.0798 0.0803 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.102 0.104 0.103 1 week 0.120 0.120 0.120 2 weeks 0.146 0.149 0.148

EXAMPLE 2

A composition in accordance with the present invention was prepared bymixing equal amounts of quetiapine fumarate and fumaric acid, i.e., 1:1ratio. The composition was placed in an open container and subjected toaccelerated stability conditions of 60° C. and 60% humidity for twoweeks. The impurity profile of the composition was determined by HPLC asfollows:

% Unknown Impurity with RRT* 0.33 Time point Sample 1 Sample 2 Averageinitial 0.0158 0.0167 0.0163 1 week 0.0119 0.0127 0.0123 2 weeks 0.01370.0157 0.0147 *RRT = relative retention time

% Unknown Impurity with RRT* 0.47 Time point Sample 1 Sample 2 AverageInitial 0.0322 0.0328 0.0325 1 week 0.0309 0.0309 0.0309 2 weeks 0.03300.0337 0.0334 *RRT = relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0708 0.0698 0.0703 1 week 0.0698 0.0697 0.0698 2 weeks 0.07260.0721 0.0724 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.119 0.119 0.119 1 week 0.113 0.114 0.114 2 weeks 0.119 0.121 0.120

COMPARATIVE EXAMPLE 1

A composition not in accordance with the present invention was preparedby mixing equal amounts of quetiapine fumarate and citric acidmonohydrate, i.e., 1:1 ratio. The composition was placed in an opencontainer and subjected to accelerated stability conditions of 60° C.and 60% humidity for two weeks. The impurity profile of the compositionwas determined by HPLC as follows:

% Unknown Impurity with RRT* 0.33 Time point Sample 1 Sample 2 Averageinitial 0.0100 0.0097 0.0099 1 week 17.3115 20.668 18.9898 2 weeks17.4295 19.3841 18.4068 *RRT = relative retention time

% Unknown Impurity with RRT* 0.36 Time point Sample 1 Sample 2 AverageInitial Below Detectable Below Detectable Below Detectable limits limitslimits 1 week 8.2142 10.794 9.5041 2 weeks 14.1043 18.4762 16.2903 *RRT= relative retention time

% Unknown Impurity with RRT* 0.47 Time point Sample 1 Sample 2 Averageinitial 0.0323 0.0324 0.0324 1 week 0.0136 0.0136 0.0136 2 weeks 0.01610.0502 0.0332 *RRT = relative retention time

% Unknown Impurity with RRT* 0.53 Time point Sample 1 Sample 2 Averageinitial — — — 1 week 0.0340 0.0757 0.0549 2 weeks 0.0837 0.2570 0.1704*RRT = relative retention time

% Unknown Impurity with RRT* 0.59 Time point Sample 1 Sample 2 AverageInitial — — — 1 week 0.2615 0.3827 0.3221 2 weeks 0.3943 0.7645 0.5794*RRT = relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0702 0.0692 0.0697 1 week 0.0566 0.0538 0.0552 2 weeks 0.05330.0585 0.0559 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.112 0.112 0.112 1 week 25.891 31.987 28.939 2 weeks 32.081 38.99035.5355

COMPARATIVE EXAMPLE 2

A composition not in accordance with the present invention was preparedby mixing equal amounts of quetiapine fumarate and monosodium dihydrogencitrate, i.e., 1:1 ratio. The composition was placed in an opencontainer and subjected to accelerated stability conditions of 60° C.and 60% humidity for two weeks. The impurity profile of the compositionwas determined by HPLC as follows:

% Unknown Impurity with RRT* 0.47 Time point Sample 1 Sample 2 Averageinitial 0.0357 0.0327 0.0342 1 week 0.0295 0.0318 0.0307 2 weeks 0.03510.0361 0.0356 *RRT = relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0700 0.0688 0.0694 1 week 0.0699 0.0687 0.0693 2 weeks 0.07250.0739 0.0732 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.106 0.101 0.104 1 week 0.100 0.100 0.100 2 weeks 0.108 0.110 0.109

COMPARATIVE EXAMPLE 3

A composition not in accordance with the present invention was preparedby mixing equal amounts of quetiapine fumarate and tartaric acid, i.e.,1:1 ratio. The composition was placed in an open container and subjectedto accelerated stability conditions of 60° C. and 60% humidity for twoweeks. The impurity profile of the composition was determined by HPLC asfollows:

% Unknown Impurity with RRT* 0.33 Time point Sample 1 Sample 2 Averageinitial 0.0137 0.0146 0.0142 1 week 0.0363 0.0374 0.0369 2 weeks 0.18130.1947 0.1880 *RRT = relative retention time

% Unknown Impurity with RRT* 0.50 Time point Sample 1 Sample 2 AverageInitial 0.0345 0.0341 0.0343 1 week 0.9724 1.0025 0.9875 2 weeks 2.94223.1656 3.0539 *RRT = relative retention time

% Unknown Impurity with RRT* 0.59 Time point Sample 1 Sample 2 Averageinitial — — — 1 week 0.0422 0.0424 0.0423 2 weeks 0.1856 0.1953 0.1905*RRT = relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0700 0.0705 0.0703 1 week 0.0688 0.0696 0.0692 2 weeks 0.07010.0705 0.0703 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.118 0.119 0.1185 1 week 1.120 1.151 1.136 2 weeks 3.379 3.625 3.502

COMPARATIVE EXAMPLE 4

A composition not in accordance with the present invention was preparedby mixing equal amounts of quetiapine fumarate and maleic acid, i.e.,1:1 ratio. The composition was placed in an open container and subjectedto accelerated stability conditions of 60° C. and 60% humidity for twoweeks. The impurity profile of the composition was determined by HPLC asfollows:

% Unknown Impurity with RRT* 0.33 Time point Sample 1 Sample 2 Averageinitial 0.0137 0.0136 0.0137 1 week 0.1411 0.1536 0.1474 2 weeks 0.31280.3628 0.3378 *RRT = relative retention time

% Unknown Impurity with RRT* 0.36 Time point Sample 1 Sample 2 AverageInitial Below Detectable Below Detectable Below Detectable limits limitslimits 1 week 0.5761 0.6746 0.6254 2 weeks 1.2091 1.4720 1.3406 *RRT =relative retention time

% Unknown Impurity with RRT* 0.41 Time point Sample 1 Sample 2 Averageinitial Below Detectable Below Detectable Below Detectable limits limitslimits 1 week Below Detectable Below Detectable Below Detectable limitslimits limits 2 weeks 0.0633 0.0508 0.0571 *RRT = relative retentiontime

% Unknown Impurity with RRT* 0.48~0.51 Time point Sample 1 Sample 2Average initial 0.0347 0.0332 0.0340 1 week 0.3403 0.3977 0.3690 2 weeks0.8782 1.0318 0.9550 *RRT = relative retention time

% Unknown Impurity with RRT* 0.55~0.59 Time point Sample 1 Sample 2Average Initial Below Detectable Below Detectable Below Detectablelimits limits limits 1 week 68.9090 73.5815 71.2453 2 weeks 76.655479.3466 78.001 *RRT = relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0694 0.0700 0.0697 1 week 0.0420 0.0363 0.0392 2 weeks 0.03940.0343 0.0369 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.118 0.117 0.118 1 week 70.008 74.844 72.426 2 weeks 79.158 82.29880.728

COMPARATIVE EXAMPLE 5

A composition not in accordance with the present invention was preparedby mixing equal amounts of quetiapine fumarate and malic acid, i.e., 1:1ratio. The composition was placed in an open container and subjected toaccelerated stability conditions of 60° C. and 60% humidity for twoweeks. The impurity profile of the composition was determined by HPLC asfollows:

% Unknown Impurity with RRT* 0.27~0.33 Time point Sample 1 Sample 2Average initial 0.0142 0.0147 0.0145 1 week 0.762 0.832 0.797 2 weeks1.7530 1.5296 1.6413 *RRT = relative retention time

% Unknown Impurity with RRT* 0.36 Time point Sample 1 Sample 2 AverageInitial Below Detectable Below Detectable Below Detectable limits limitslimits 1 week 4.971 5.591 5.281 2 weeks 9.6604 8.6327 9.1466 *RRT =relative retention time

% Unknown Impurity with RRT* 0.48~0.50 Time point Sample 1 Sample 2Average initial 0.0335 0.0336 0.0336 1 week 29.6478 34.3748 32.0113 2weeks 41.9445 38.6429 40.2937 *RRT = relative retention time

% Unknown Impurity with RRT* 0.59 Time point Sample 1 Sample 2 AverageInitial 1 week 1.2120 1.4466 1.3293 2 weeks 2.4228 2.3229 2.3729 *RRT =relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0686 0.0696 0.0691 1 week 0.0590 0.0556 0.0573 2 weeks 0.09210.0930 0.0926 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.117 0.117 0.117 1 week 36.652 42.299 39.476 2 weeks 55.873 51.22153.547

COMPARATIVE EXAMPLE 6

A composition not in accordance with the present invention was preparedby mixing equal amounts of quetiapine fumarate and sodium hydrogentartrate monohydrate, i.e., 1:1 ratio. The composition was placed in anopen container and subjected to accelerated stability conditions of 60°C. and 60% humidity for two weeks. The impurity profile of thecomposition was determined by HPLC as follows:

% Unknown Impurity with RRT* 0.47 Time point Sample 1 Sample 2 Averageinitial 0.0357 0.0377 0.0367 1 week 0.0363 0.0374 0.0369 2 weeks 0.03520.0375 0.0364 *RRT = relative retention time

% Unknown Impurity with RRT* 0.89 Time point Sample 1 Sample 2 Averageinitial 0.0705 0.0696 0.0701 1 week 0.0700 0.0713 0.0707 2 weeks 0.07190.0729 0.0724 *RRT = relative retention time

% Total Unknown Impurities Time point Sample 1 Sample 2 Average initial0.106 0.107 0.107 1 week 0.106 0.109 0.108 2 weeks 0.107 0.110 0.109

EXAMPLE 3

A pharmaceutical composition and controlled release dosage form inaccordance with the present invention was prepared as follows:

Approximately 75 grams of Lactitol NF was dissolved in approximately 145grams of purified water to prepare a Lactitol solution.

Approximately 1151.3 grams of quetiapine hemifumarate that had beensieved through a 120 mesh sieve and approximately 810.0 grams ofsuccinic acid that had been sieved through a 80 mesh sieve were mixedfor about 5 minutes. The mixture was than sprayed with 200 ml of theLactitol solution to create granules. The granules were dried and sizedwith granules smaller than 20 mesh being discarded.

Approximately 203.63 grams of the dried and sized granules were thenblended with approximately 20.7 grams of LUBRITAB (hydrogenatedvegetable oil), 2.3 grams of talc and 1.15 grams of colloidal silicondioxide for about 15 minutes in a V type blender. Approximately 2.3grams of magnesium stearate was added to the blend and further blendedfor about 5 minutes.

The blend was then compressed into controlled release quetiapine tabletsusing a rotary tablet press with an 8*16 mm capsule shaped die.

A placebo rate controlling layer was subsequently compressed onto oneside of the controlled released quetiapine tablet using a rotary tabletpress. The placebo rate controlling layer was prepared from granulesobtained by mixing approximately 39.5 grams of lactose NF, 10 grams ofLUBRITAB and 0.5 grams of talc in a V type blender.

A 200 mg controlled release quetiapine tablet in accordance with thepresent invention and without any materials that gel or swell wereplaced in an aqueous environment according to the above procedure withthe following composition:

Ingredient % w/w Mg/tablet Quetiapine 41.09 230.26 Hemifumarate SuccinicAcid 28.93 162.11 Lactitol 2.68 15.01 LUBRITAB 7.39 41.43 ColloidalSilicon Dioxide 0.41 2.31 Magnesium Stearate 0.82 4.61 Talc 0.82 4.61Active Tablet Subtotal 82.15 460.33 Lactose 14.10 79.0 LUBRITAB 3.5720.0 Talc 0.18 1.0 Placebo Layer Subtotal 17.85 100.0 Total 100.0 560.33

Three (3) of the 200 mg controlled release dosage forms prepared inExample 3 were tested according to the procedures described in UnitedStates Pharmacopeia 29 using a Type I (basket) apparatus at 37° C., 100rpms and 900 ml of 0.1N HCl. The release profile determined by thetesting was:

Time % Released 2 hours 44.7 4 hours 61.1 6 hours 73.0 8 hours 82.1 12hours  94.2 18 hours  98.7 24 hours  100.4

The pH of the tablet prepared in Example 3 was measured by preparing a1% weight by volume aqueous suspension and a 5% weight by volume aqueoussuspension of the tablet ingredients at 25° C. The tablet ingredientswere in a powder form, i.e not tableted, and suspended in purifiedwater. The pH was measured using a commercially available pH probe anddetermined to be 3.68 for the 1% suspension and 3.46 for the 5%suspension.

EXAMPLE 4

A pharmaceutical composition and controlled release dosage form inaccordance with the present invention was prepared according to theprocedure described in Example 3 with the following composition:

Ingredient % w/w Mg/tablet Quetiapine 41.3 230.26 Hemifumarate SuccinicAcid 29.0 162 Lactitol 2.7 15 LUBRITAB 7.4 41.4 Magnesium Stearate 0.84.6 Talc 0.8 4.6 Active Tablet Subtotal 82.1 457.86 Lactose 14.2 79.0LUBRITAB 3.6 20.0 Talc 0.2 1.0 Placebo Layer Subtotal 17.9 100.0 Total100.0 557.9

Three (3) of the 200 mg controlled release dosage forms prepared inExample 4 were tested according to the procedures described in UnitedStates Pharmacopeia 29 using a Type I (basket) apparatus at 37° C., 100rpms and 900 ml of 0.1N HCl. The release profile determined by thetesting was:

Time % Released 2 hours 43.6 4 hours 59.3 6 hours 71.1 8 hours 80.5 12hours  92.0 18 hours  96.6 24 hours  98.4

EXAMPLES 5-7

Pharmaceutical compositions and controlled release dosage forms inaccordance with the present invention were prepared according to theprocedure described in Example 3 with the following composition:

Ingredient Mg/tablet (Ex 5) Mg/tablet (Ex 6) Mg/tablet (Ex 7) Quetiapine57.56 345.38 460.51 Hemifumarate Succinic Acid 38.38 243.17 307.06Lactitol 3.75 22.52 30.01 LUBRITAB 24.11 60.00 55.41 Colloidal 0.64 3.504.37 Silicon Dioxide Magnesium 1.27 6.90 8.75 Stearate Talc 1.27 6.908.75 Active Tablet 126.98 688.36 874.86 Subtotal Lactose 28.44 79.0094.80 LUBRITAB 7.20 20.0 24.0 Talc 0.36 1.0 1.20 Placebo Layer 36.00100.0 120.0 Subtotal Total 162.98 788.36 994.86

The pH of the tablets prepared in Examples 6 and 7 were determinedaccording to the procedure described in Example 3. The pH of the 1%suspension of Example 6 was 3.65 and the pH of the 5% suspension ofExample 6 was 3.46. The pH of the 1% suspension of Example 7 was 3.67and the pH of the 5% suspension of Example 7 was 3.5.

EXAMPLES 8-9

Pharmaceutical compositions and immediate release dosage forms inaccordance with the present invention were prepared according to theprocedure described in Example 3 with the following composition:

Ingredient Mg/Tablet (Ex 8) Mg/tablet (Ex 9) Quetiapine 230.26 230.26Hemifumarate Succinic Acid 162 162 Lactitol 15 15 Colloidal silicon 2.3— dioxide Magnesium Stearate 4.6 4.6 Talc 4.6 4.6 Active Tablet Subtotal418.76 416.46 Lactose 79.2 79.2 Talc 0.8 0.8 Placebo Layer Subtotal 8080 Total 498.8 496.5

Three (3) of the 200 mg controlled release dosage forms prepared inExamples 8 and 9 were tested according to the procedures described inUnited States Pharmacopeia 29 using a Type I (basket) apparatus at 37°C., 100 rpms and 900 ml of 0.1N HCl. The release profile determined bythe testing was:

Ex 8 Ex9 Time % Released % Released 0.75 hours 99.0 95.6   1 hours 99.195.5

EXAMPLE 10 (PROPHETIC)

A pharmaceutical composition and immediate release dosage form inaccordance with the present invention can be prepared according to theprocedure described in Example 3 with the following composition:

Ingredient Mg/Tablet (Ex 8) Mg/tablet (Ex 9) Quetiapine 230.26 230.26Hemifumarate Fumaric Acid 162 162 Lactitol 15 15 Colloidal silicon 2.3 —dioxide Magnesium Stearate 4.6 4.6 Talc 4.6 4.6 Active Tablet Subtotal418.76 416.46 Lactose 79.2 79.2 Talc 0.8 0.8 Placebo Layer Subtotal 8080 Total 498.8 496.5

EXAMPLES 11-13 (PROPHETIC)

Pharmaceutical compositions and controlled release dosage forms inaccordance with the present invention can be prepared according to theprocedure described in Example 3 with the following composition:

Ingredient Mg/tablet (Ex 11) Mg/tablet (Ex 12) Mg/tablet (Ex 13)Quetiapine 230.26 345.38 460.51 Hemifumarate Fumaric Acid 162.11 243.17307.06 Lactitol 15.01 22.52 30.01 LUBRITAB 41.43 60.00 55.41 Colloidal2.31 3.50 4.37 Silicon Dioxide Magnesium 4.61 6.90 8.75 Stearate Talc4.61 6.90 8.75 Active Tablet 460.33 688.36 874.86 Subtotal Lactose 79.079.00 94.80 LUBRITAB 20.0 20.0 24.0 Talc 1.0 1.0 1.20 Placebo Layer100.00 100.0 120.0 Subtotal Total 560.33 788.36 994.86

While certain preferred and alternative embodiments of the presentinvention have been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

1. A pharmaceutical composition comprising: (i) an atypicalantipsychotic drug and (ii) an organic acid selected from the groupconsisting of succinic acid, fumaric acid and mixtures thereof whereinthe pH of a 1% weight by volume aqueous solution of suspension of thecomposition is less than
 5. 2. The composition as defined in claim 1wherein the composition further comprises at least one pharmaceuticallyacceptable excipient.
 3. The composition as defined in claim 1 whereinthe atypical antipsychotic drug is selected from the group consisting ofclozapine, olanzapine, risperidone, quetiapine, ziprasidone,paliperidone, aripiprazole, asenapine, iloperidone, sertindole,zotepine, amisulpride bifeprunox, melperone and pharmaceuticallyacceptable salts, isomers and metabolites thereof.
 4. The composition asdefined in claim 3 wherein the atypical antipsychotic drug isolanzapine, quetiapine or pharmaceutically acceptable salts thereof. 5.The composition as defined in claim 4 wherein the atypical antipsychoticdrug is quetiapine hydrochloride or quetiapine fumarate.
 6. Thecomposition as defined in claim 1 wherein the pH is less than
 4. 7. Thecomposition as defined in claim 1 wherein the organic acid is succinicacid.
 8. The composition as defined in claim 1 wherein the organic acidis fumaric acid.
 9. The composition as defined in claim 1 wherein thecomposition is a mixture of succinic acid and fumaric acid.
 10. Thecomposition as defined in claim 1 wherein the composition is a solidoral dosage form.
 11. The composition as defined in claim 10 wherein thecomposition is a solid oral controlled release dosage form.
 12. Thecomposition as defined in claim 11 wherein the solid oral controlledrelease dosage form is a hydrophobic matrix that is free of any materialthat gels or swells.
 13. An oral solid controlled release dosage formcomprising: (i) an atypical antipsychotic drug; (ii) an organic acidselected from the group consisting of succinic acid, fumaric acid ormixtures thereof; and (iii) a rate controlling excipient, wherein the pHof a 1% weight by volume aqueous solution of suspension of the dosageform is less than
 5. 14. The solid controlled release dosage form asdefined in claim 13 wherein the dosage form is a matrix tablet.
 15. Thesolid controlled release dosage form as defined in claim 14 wherein therate controlling excipient is a hydrophobic material.
 16. The solidcontrolled release dosage form as defined in claim 14 wherein the ratecontrolling excipient is a hydrophilic material.
 17. The solidcontrolled release dosage form as defined in claim 13 wherein theatypical antipsychotic drug is selected from the group consisting ofclozapine, olanzapine, risperidone, quetiapine, ziprasidone,paliperidone, aripiprazole, asenapine, iloperidone, sertindole,zotepine, amisulpride bifeprunox, melperone and pharmaceuticallyacceptable salts, isomers and metabolites thereof.
 18. The solidcontrolled release dosage from as defined in claim 17 wherein theatypical antipsychotic drug is olanzapine, quetiapine orpharmaceutically acceptable salts thereof.
 19. The solid controlledrelease dosage form as defined in claim 18 wherein atypicalantipsychotic drug is quetiapine hydrochloride or quetiapine fumarate.20. The solid controlled release dosage form as defined in claim 13wherein pH is less than
 4. 21. The solid controlled release dosage formas defined in claim 14 wherein matrix is free of any material that gelsor swells.
 22. The solid controlled release dosage form as defined inclaim 13 wherein the organic acid is succinic acid.
 23. The solidcontrolled release dosage form as defined in claim 13 wherein theorganic acid is fumaric acid.
 24. The solid controlled release dosageform as defined in claim 13 wherein the organic acid is a mixture ofsuccinic and fumaric acid.